Mycosis is a disease caused by a fungus which infects to human or animals. As representative mycoses in human, there have been known candidiasis due to Candida, cryptococcosis due to Ccusryptococ, aspergillosis due to Aspergillus, zygomycosis due to Zygomycetes, dermatophytosis (trichophytia) due to Trichophyton, and the like (pathogenic fungi and mycosis (NANZANDO Co., Ltd., Revised 2nd Edition), pp. 42-45; Non-Patent Document 1).
Trichophyton which is one of pathogenic fungi of mycosis is dermatophyte which could be pathogenic fungi of trichophytia, and has the keratolytic ability. According to this ability, it invades into a skin, nail or hair to cause trichophytia (Pathogenic fungi and mycosis (NANZANDO Co., Ltd., Revised 2nd Edition), pp. 184-187; Non-Patent Document 2).
Tinea unguium is a disease of a nail caused by dermatophyte, and a disease accompanied by symptoms of turbidity, thickening, destruction, and deformation, etc. of the nail plate. At present, it is said that there is one patient per ten Japaneses, and about 12 million patients in total. This is a disease frequently appearing in aged person, and a further increase in a number of patients will be concerned in the future. There is a report that a diabetic patient easily contracts the disease so that the possibility of causing serious complications is being pointed out.
As a treatment method of onychomycosis in Japan nowadays, only an oral medicine of an antifungal agent (itraconazole and terbinafine, etc.) has been approved. However, the antifungal agent for oral administration has been pointed out that it has drug interaction, liver damage, and side effect(s) due to long term administration. In addition, an aged person, diabetic patient, etc., having a high morbidity of tinea unguium often takes multiple types of drugs, so that oral administration of the anti-fungal agent for the treatment of tinea unguium is difficult in many cases (Br. J. of Dermatol., vol. 139 (4), p. 665, 1998; Non-Patent Document 3).
As for an anti-dermatophytosis drug for external use, to exert the medical effect of the anti-dermatophytosis drug for external use, it is required to deliver the drug to an epidermal horny layer and a nail which are infected portions, with a high level of a drug concentration in addition to have the drug itself having a potent antifungal activity against dermatophytes. However, the antifungal drug for external use to be used for usual skin mycosis cannot reach to the horny or inside of the nail, or to a nail matrix with a sufficient concentration, whereby a sufficient effect cannot be obtained.
In abroad, a nail lacquer for external use of amorolfine or ciclopirox has been approved and used. However, their permeabilities into the nail are very low, so that it cannot be expected to deliver to nail matrix cells by further permeation.
Therefore, a patch for external use of dermatophytosis such as tinea unguium, etc., is required to have not only a potent antifungal activity against dermatophytes, but also high permeability to a nail, but such a patch for external use has not yet been found out.
On the other hand, as a compound having a 2-(1H-pyrazol-1-yl)phenol backbone, 2-(3,5-dimethyl-1H-pyrazol-1-yl)phenol which has methyl groups at the 3-position and 5-position of the pyrazole ring has been known (Annual Report of Takeda Research Center (1963) 22, p. 27; Non-Patent Document 4). These compounds are directed to prevent growth of Mycobacterium tuberculosis in human. However, in Non-Patent Document 4, there is no disclosure of the 2-(1H-pyrazol-1-yl)phenol compound other than 2-(3,5-dimethyl-1H-pyrazol-1-yl)phenol.
As the compound having a 2-(1H-pyrazol-1-yl)phenol backbone other than 2-(3,5-dimethyl-1H-pyrazol-1-yl)phenol, 2-(1H-pyrazol-1-yl)phenol, 2-(3,5-dimethyl-1H-pyrazol-1-yl)-1,4-benzenediol and 2-(4-chloro-3,5-dimethyl-1H-pyrazol-1-yl)-1,4-benzenediol have been known. These have been utilized for various kinds of chemical reactions, a starting material as a compound for electroluminescence devices (JP Patent No. 4284169: Patent Document 1), a photostabilizer (Spanish Patent Laid-Open No. 20158648A: Patent Document 2), etc. Also, in WO 2003/005999 (Patent Document 3), 2-(5-amino-3-tert-butyl-1H-pyrazol-1-yl)-5-methylphenol is disclosed.
However, in these prior art literatures, there is neither suggestion nor disclosure about its antifungal activity against dermatophytes of the compound having a 2-(1H-pyrazol-1-yl)phenol backbone.